FDA’s Dapagliflozin Review to Focus on Hepatic Effects, Cancer Risks

Dapagliflozin seems to have skirted the cardiovascular safety concerns surrounding other agents intended for treating type 2 diabetes, but the Food and Drug Administration is nevertheless seeking advisory committee input on a handful of “unexpected” safety issues for the first-in-class sodium glucose cotransporter–2 inhibitor, including potential hepatic and cancer risks.

At a July 19 meeting, the agency will ask its Endocrinologic and Metabolic Drugs Advisory Committee whether sufficient evaluation has been conducted preapproval to determine if dapagliflozin is associated with a risk of hepatotoxicity, according to agency briefing documents released July 15.

The FDA also seeks panel discussion on numeric imbalances in cases of breast and bladder cancer observed in the clinical program, and it asks the committee to weigh the clinical significance of other safety findings, including the increased risk of genitourinary infections.

The agency has little quibble with dapagliflozin’s efficacy, other than to say it is limited to patients with normal renal function or only mild impairment. However, the FDA asks whether additional studies in special populations should be conducted to better characterize efficacy or whether renal function monitoring should be performed before and during treatment.

Novel Mechanism of Action

Dapagliflozin is the most advanced member of the new class of oral sodium glucose cotransporter–2 (SGLT2) inhibitors that cause renal elimination of glucose. The mechanism of action, which offers a way to lower blood glucose apart from insulin, has spurred predictions that the class would find its niche as add-on therapy at different stages of the disease.

Bristol-Myers Squibb and AstraZeneca are seeking a broad indication for dapagliflozin: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The new drug application submission included data from three phase IIb and 11 phase III studies evaluating dapagliflozin as monotherapy, add-on therapy to metformin, sulfonylureas, pioglitazone (Actos), or insulin, as well as initial combination therapy with metformin. Efficacy results were comparable to those for existing agents, the FDA says.

“The magnitude of glycemic reduction in the clinical trials has been consistent and in line with recently approved antidiabetic drugs, such as dipeptidyl peptidase inhibitors,” the division of metabolism and endocrinology products says in its clinical briefing document. “In active-controlled trials, dapagliflozin demonstrated equivalent effects on HbA_1c as near maximally effective doses of metformin and glipizide at 1 year.”

However, the agency found efficacy to be limited in those patients with compromised renal function. The sponsors have proposed that the drug not be used in patients with moderate renal impairment, with a glomerular filtration rate (GFR) less than 45 mL/min per 1.73 m². But the agency cited a loss of statistically significant efficacy in patients with more mild impairment, with a GFR less than 45-59 mL/min per 1.73 m².

The loss of efficacy that accompanies an increase in renal impairment is particularly important for type 2 diabetics, FDA reviewers say.

“It is important to note that patients with [type 2 diabetes mellitus] are at risk for worsening renal function over the course of their disease. Unlike treatment with other classes of antidiabetic medications that rely on either insulin secretion or sensitivity, dapagliflozin’s effect is dependent on GFR and independent of beta-cell function. Therefore, secondary failure of glycemic control with dapagliflozin may represent deterioration of renal function, rather than beta-cell function, and discontinuation of dapagliflozin (in contrast to the practice of adding drugs of complementary effects) may be recommended.”

Cardiovascular Profile Looks Good

Concerns about the postmarketing cardiovascular (CV) safety of another diabetes drug, GlaxoSmithKline’s Avandia (rosiglitazone), spurred new FDA guidelines in December 2008 requiring sponsors to rule out an unacceptable level of increased cardiovascular risk before and after approval for type 2 treatments.

Sponsors must rule out an 80% increased risk of major adverse CV events preapproval. If preapproval clinical data show that the upper bound of the two-sided 95% confidence interval for the estimated risk lies between 1.3 and 1.8, companies generally will need to conduct a postmarketing trial to demonstrate that the upper bound is less than 1.3. If the preapproval data demonstrate an upper bound below 1.3, a postmarketing cardiovascular trial generally may not be necessary.

The guidance’s provisions applied to all drugs pending FDA review and in clinical development at the time it was issued. The new CV requirements tripped up at least one antidiabetic agent that had already been submitted for FDA review, Takeda’s DPP-4 inhibitor alogliptin.

However, it appears that dapagliflozin has easily overcome the preapproval CV hurdle laid out in the guidance.

Based on a meta-analysis of the phase II/III trials, the drug “does not appear to be associated with excess CV risk with an overall HR of 0.67 … relative to comparators for the primary composite of CV deaths, myocardial infarctions, stroke, and hospitalization for unstable angina,” Dr. Mary Parks, director of the division of metabolism and endocrinology products, writes in her memo to the advisory committee.

Although the upper bound of the 95% confidence interval was below 1.3, falling shy of the cut point for a mandatory postapproval CV outcomes trial, the FDA nevertheless has decided such a study will be required.

“The applicant has proposed to conduct a CV outcomes trial whose primary objective is to demonstrate a cardioprotective effect of dapagliflozin,” Dr. Parks writes. “FDA concurs with the applicant that a CV outcomes trial is necessary to better characterize the CV safety of this drug and to evaluate safety issues that have arisen in the course of this [new drug application] review. If approved, this CV outcomes trial will be a required postmarketing trial.”

But Hepatic, Cancer Concerns Worry

Although dapagliflozin’s premarketing CV profile looks clean, “several unexpected safety issues identified in this clinical development program were of sufficient concern to FDA to merit discussion of their impact on the overall benefit-risk consideration,” Dr. Parks writes.

Among these are the drug’s hepatic effects. There were a total of five dapagliflozin-treated patients in the phase IIb/III trials who met the laboratory criteria for Hy’s Law (AST or ALT levels greater than three times the upper limit of normal and elevation of total bilirubin level greater than two times the upper limit of normal). One of these was classified as a “probable” case of drug-induced liver injury.

In their review, Office of Surveillance and Epidemiology hepatologists Leonard Seeff and John Senior noted that in many cases the data were too limited to make a linkage between dapagliflozin and liver damage. Given the importance of recognizing sentinel cases of drug-induced liver injury in registrational trials, “it is prudent to gather more information on all relevant cases as part of an in-depth review of the dapagliflozin [new drug application] in order to assess whether this agent may be hepatotoxic,” they say, adding that careful hepatic monitoring should be performed in any future studies.

The FDA also calls the committee’s attention to numerical imbalances in cases of breast and bladder cancer among dapagliflozin-treated patients.

There were seven bladder cancer cases in dapagliflozin-treated patients at the time of the 4-month safety update, compared with none in the control group. Subsequently, two more cases were reported with dapagliflozin and one with controls. “This can be extrapolated to 207 cases per 100,000 person-year exposure in dapagliflozin-treated patients versus 53 cases per 100,000 person-year exposure in control[s],” the clinical review states.

The findings suggest dapagliflozin could be in for the same type of bladder cancer cloud currently hanging over Actos.

The FDA questions whether detection bias resulting from dapagliflozin’s mechanism of action and related genitourinary adverse effects could have contributed to the imbalance observed.

“More frequent assessments of urinalysis in the dapagliflozin group might result in postbaseline detection of hematuria requiring further work-up and higher rate of cancer diagnosis than control group, which might not have received as extensive monitoring,” the FDA reviewers state.

“In this regard, it is interesting to note that concerns of bladder cancer associated with pioglitazone use arose during premarketing development due to nonclinical findings of bladder cancer in male rodents. This led to a prospective assessment of urine cytology in approximately 1,800 patients in clinical trials up to 1 year [in] duration. Despite similar active surveillance for bladder cancer in pioglitazone and control groups, no clinical cases were detected premarketing. Imbalance of clinical bladder cancer risk with pioglitazone was not observed until after approval.”

There also was an imbalance in the number of breast cancer cases, with nine reported in the dapagliflozin-treated group and none in the control group.

For both types of cancer, the FDA concludes that the numbers observed exceeded the expected number of cases in the type 2 diabetic population. It asks the advisory committee whether any imbalance in baseline factors may have contributed to the findings and whether detection bias was a factor.

The FDA also wants the committee to consider the increase in genital and urinary infections associated with dapagliflozin. Such infections have become a well-known side effect of this class of drugs, given their mechanism of action.

This coverage is provided by “The Pink Sheet.” This news organization and “The Pink Sheet” are owned by Elsevier.

Dapagliflozin seems to have skirted the cardiovascular safety concerns surrounding other agents intended for treating type 2 diabetes, but the Food and Drug Administration is nevertheless seeking advisory committee input on a handful of “unexpected” safety issues for the first-in-class sodium glucose cotransporter–2 inhibitor, including potential hepatic and cancer risks.

At a July 19 meeting, the agency will ask its Endocrinologic and Metabolic Drugs Advisory Committee whether sufficient evaluation has been conducted preapproval to determine if dapagliflozin is associated with a risk of hepatotoxicity, according to agency briefing documents released July 15.

The FDA also seeks panel discussion on numeric imbalances in cases of breast and bladder cancer observed in the clinical program, and it asks the committee to weigh the clinical significance of other safety findings, including the increased risk of genitourinary infections.

The agency has little quibble with dapagliflozin’s efficacy, other than to say it is limited to patients with normal renal function or only mild impairment. However, the FDA asks whether additional studies in special populations should be conducted to better characterize efficacy or whether renal function monitoring should be performed before and during treatment.

Novel Mechanism of Action

Dapagliflozin is the most advanced member of the new class of oral sodium glucose cotransporter–2 (SGLT2) inhibitors that cause renal elimination of glucose. The mechanism of action, which offers a way to lower blood glucose apart from insulin, has spurred predictions that the class would find its niche as add-on therapy at different stages of the disease.

Bristol-Myers Squibb and AstraZeneca are seeking a broad indication for dapagliflozin: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The new drug application submission included data from three phase IIb and 11 phase III studies evaluating dapagliflozin as monotherapy, add-on therapy to metformin, sulfonylureas, pioglitazone (Actos), or insulin, as well as initial combination therapy with metformin. Efficacy results were comparable to those for existing agents, the FDA says.

“The magnitude of glycemic reduction in the clinical trials has been consistent and in line with recently approved antidiabetic drugs, such as dipeptidyl peptidase inhibitors,” the division of metabolism and endocrinology products says in its clinical briefing document. “In active-controlled trials, dapagliflozin demonstrated equivalent effects on HbA_1c as near maximally effective doses of metformin and glipizide at 1 year.”

However, the agency found efficacy to be limited in those patients with compromised renal function. The sponsors have proposed that the drug not be used in patients with moderate renal impairment, with a glomerular filtration rate (GFR) less than 45 mL/min per 1.73 m². But the agency cited a loss of statistically significant efficacy in patients with more mild impairment, with a GFR less than 45-59 mL/min per 1.73 m².

The loss of efficacy that accompanies an increase in renal impairment is particularly important for type 2 diabetics, FDA reviewers say.

“It is important to note that patients with [type 2 diabetes mellitus] are at risk for worsening renal function over the course of their disease. Unlike treatment with other classes of antidiabetic medications that rely on either insulin secretion or sensitivity, dapagliflozin’s effect is dependent on GFR and independent of beta-cell function. Therefore, secondary failure of glycemic control with dapagliflozin may represent deterioration of renal function, rather than beta-cell function, and discontinuation of dapagliflozin (in contrast to the practice of adding drugs of complementary effects) may be recommended.”

Cardiovascular Profile Looks Good

Concerns about the postmarketing cardiovascular (CV) safety of another diabetes drug, GlaxoSmithKline’s Avandia (rosiglitazone), spurred new FDA guidelines in December 2008 requiring sponsors to rule out an unacceptable level of increased cardiovascular risk before and after approval for type 2 treatments.

Sponsors must rule out an 80% increased risk of major adverse CV events preapproval. If preapproval clinical data show that the upper bound of the two-sided 95% confidence interval for the estimated risk lies between 1.3 and 1.8, companies generally will need to conduct a postmarketing trial to demonstrate that the upper bound is less than 1.3. If the preapproval data demonstrate an upper bound below 1.3, a postmarketing cardiovascular trial generally may not be necessary.

The guidance’s provisions applied to all drugs pending FDA review and in clinical development at the time it was issued. The new CV requirements tripped up at least one antidiabetic agent that had already been submitted for FDA review, Takeda’s DPP-4 inhibitor alogliptin.

However, it appears that dapagliflozin has easily overcome the preapproval CV hurdle laid out in the guidance.

Based on a meta-analysis of the phase II/III trials, the drug “does not appear to be associated with excess CV risk with an overall HR of 0.67 … relative to comparators for the primary composite of CV deaths, myocardial infarctions, stroke, and hospitalization for unstable angina,” Dr. Mary Parks, director of the division of metabolism and endocrinology products, writes in her memo to the advisory committee.

Although the upper bound of the 95% confidence interval was below 1.3, falling shy of the cut point for a mandatory postapproval CV outcomes trial, the FDA nevertheless has decided such a study will be required.

“The applicant has proposed to conduct a CV outcomes trial whose primary objective is to demonstrate a cardioprotective effect of dapagliflozin,” Dr. Parks writes. “FDA concurs with the applicant that a CV outcomes trial is necessary to better characterize the CV safety of this drug and to evaluate safety issues that have arisen in the course of this [new drug application] review. If approved, this CV outcomes trial will be a required postmarketing trial.”

But Hepatic, Cancer Concerns Worry

Although dapagliflozin’s premarketing CV profile looks clean, “several unexpected safety issues identified in this clinical development program were of sufficient concern to FDA to merit discussion of their impact on the overall benefit-risk consideration,” Dr. Parks writes.

Among these are the drug’s hepatic effects. There were a total of five dapagliflozin-treated patients in the phase IIb/III trials who met the laboratory criteria for Hy’s Law (AST or ALT levels greater than three times the upper limit of normal and elevation of total bilirubin level greater than two times the upper limit of normal). One of these was classified as a “probable” case of drug-induced liver injury.

In their review, Office of Surveillance and Epidemiology hepatologists Leonard Seeff and John Senior noted that in many cases the data were too limited to make a linkage between dapagliflozin and liver damage. Given the importance of recognizing sentinel cases of drug-induced liver injury in registrational trials, “it is prudent to gather more information on all relevant cases as part of an in-depth review of the dapagliflozin [new drug application] in order to assess whether this agent may be hepatotoxic,” they say, adding that careful hepatic monitoring should be performed in any future studies.

The FDA also calls the committee’s attention to numerical imbalances in cases of breast and bladder cancer among dapagliflozin-treated patients.

There were seven bladder cancer cases in dapagliflozin-treated patients at the time of the 4-month safety update, compared with none in the control group. Subsequently, two more cases were reported with dapagliflozin and one with controls. “This can be extrapolated to 207 cases per 100,000 person-year exposure in dapagliflozin-treated patients versus 53 cases per 100,000 person-year exposure in control[s],” the clinical review states.

The findings suggest dapagliflozin could be in for the same type of bladder cancer cloud currently hanging over Actos.

The FDA questions whether detection bias resulting from dapagliflozin’s mechanism of action and related genitourinary adverse effects could have contributed to the imbalance observed.

“More frequent assessments of urinalysis in the dapagliflozin group might result in postbaseline detection of hematuria requiring further work-up and higher rate of cancer diagnosis than control group, which might not have received as extensive monitoring,” the FDA reviewers state.

“In this regard, it is interesting to note that concerns of bladder cancer associated with pioglitazone use arose during premarketing development due to nonclinical findings of bladder cancer in male rodents. This led to a prospective assessment of urine cytology in approximately 1,800 patients in clinical trials up to 1 year [in] duration. Despite similar active surveillance for bladder cancer in pioglitazone and control groups, no clinical cases were detected premarketing. Imbalance of clinical bladder cancer risk with pioglitazone was not observed until after approval.”

There also was an imbalance in the number of breast cancer cases, with nine reported in the dapagliflozin-treated group and none in the control group.

For both types of cancer, the FDA concludes that the numbers observed exceeded the expected number of cases in the type 2 diabetic population. It asks the advisory committee whether any imbalance in baseline factors may have contributed to the findings and whether detection bias was a factor.

The FDA also wants the committee to consider the increase in genital and urinary infections associated with dapagliflozin. Such infections have become a well-known side effect of this class of drugs, given their mechanism of action.

This coverage is provided by “The Pink Sheet.” This news organization and “The Pink Sheet” are owned by Elsevier.

Dapagliflozin seems to have skirted the cardiovascular safety concerns surrounding other agents intended for treating type 2 diabetes, but the Food and Drug Administration is nevertheless seeking advisory committee input on a handful of “unexpected” safety issues for the first-in-class sodium glucose cotransporter–2 inhibitor, including potential hepatic and cancer risks.

At a July 19 meeting, the agency will ask its Endocrinologic and Metabolic Drugs Advisory Committee whether sufficient evaluation has been conducted preapproval to determine if dapagliflozin is associated with a risk of hepatotoxicity, according to agency briefing documents released July 15.

The FDA also seeks panel discussion on numeric imbalances in cases of breast and bladder cancer observed in the clinical program, and it asks the committee to weigh the clinical significance of other safety findings, including the increased risk of genitourinary infections.

The agency has little quibble with dapagliflozin’s efficacy, other than to say it is limited to patients with normal renal function or only mild impairment. However, the FDA asks whether additional studies in special populations should be conducted to better characterize efficacy or whether renal function monitoring should be performed before and during treatment.

Novel Mechanism of Action

Dapagliflozin is the most advanced member of the new class of oral sodium glucose cotransporter–2 (SGLT2) inhibitors that cause renal elimination of glucose. The mechanism of action, which offers a way to lower blood glucose apart from insulin, has spurred predictions that the class would find its niche as add-on therapy at different stages of the disease.

Bristol-Myers Squibb and AstraZeneca are seeking a broad indication for dapagliflozin: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The new drug application submission included data from three phase IIb and 11 phase III studies evaluating dapagliflozin as monotherapy, add-on therapy to metformin, sulfonylureas, pioglitazone (Actos), or insulin, as well as initial combination therapy with metformin. Efficacy results were comparable to those for existing agents, the FDA says.

“The magnitude of glycemic reduction in the clinical trials has been consistent and in line with recently approved antidiabetic drugs, such as dipeptidyl peptidase inhibitors,” the division of metabolism and endocrinology products says in its clinical briefing document. “In active-controlled trials, dapagliflozin demonstrated equivalent effects on HbA_1c as near maximally effective doses of metformin and glipizide at 1 year.”

However, the agency found efficacy to be limited in those patients with compromised renal function. The sponsors have proposed that the drug not be used in patients with moderate renal impairment, with a glomerular filtration rate (GFR) less than 45 mL/min per 1.73 m². But the agency cited a loss of statistically significant efficacy in patients with more mild impairment, with a GFR less than 45-59 mL/min per 1.73 m².

The loss of efficacy that accompanies an increase in renal impairment is particularly important for type 2 diabetics, FDA reviewers say.

“It is important to note that patients with [type 2 diabetes mellitus] are at risk for worsening renal function over the course of their disease. Unlike treatment with other classes of antidiabetic medications that rely on either insulin secretion or sensitivity, dapagliflozin’s effect is dependent on GFR and independent of beta-cell function. Therefore, secondary failure of glycemic control with dapagliflozin may represent deterioration of renal function, rather than beta-cell function, and discontinuation of dapagliflozin (in contrast to the practice of adding drugs of complementary effects) may be recommended.”

Cardiovascular Profile Looks Good

Concerns about the postmarketing cardiovascular (CV) safety of another diabetes drug, GlaxoSmithKline’s Avandia (rosiglitazone), spurred new FDA guidelines in December 2008 requiring sponsors to rule out an unacceptable level of increased cardiovascular risk before and after approval for type 2 treatments.

Sponsors must rule out an 80% increased risk of major adverse CV events preapproval. If preapproval clinical data show that the upper bound of the two-sided 95% confidence interval for the estimated risk lies between 1.3 and 1.8, companies generally will need to conduct a postmarketing trial to demonstrate that the upper bound is less than 1.3. If the preapproval data demonstrate an upper bound below 1.3, a postmarketing cardiovascular trial generally may not be necessary.

The guidance’s provisions applied to all drugs pending FDA review and in clinical development at the time it was issued. The new CV requirements tripped up at least one antidiabetic agent that had already been submitted for FDA review, Takeda’s DPP-4 inhibitor alogliptin.

However, it appears that dapagliflozin has easily overcome the preapproval CV hurdle laid out in the guidance.

Based on a meta-analysis of the phase II/III trials, the drug “does not appear to be associated with excess CV risk with an overall HR of 0.67 … relative to comparators for the primary composite of CV deaths, myocardial infarctions, stroke, and hospitalization for unstable angina,” Dr. Mary Parks, director of the division of metabolism and endocrinology products, writes in her memo to the advisory committee.

Although the upper bound of the 95% confidence interval was below 1.3, falling shy of the cut point for a mandatory postapproval CV outcomes trial, the FDA nevertheless has decided such a study will be required.

“The applicant has proposed to conduct a CV outcomes trial whose primary objective is to demonstrate a cardioprotective effect of dapagliflozin,” Dr. Parks writes. “FDA concurs with the applicant that a CV outcomes trial is necessary to better characterize the CV safety of this drug and to evaluate safety issues that have arisen in the course of this [new drug application] review. If approved, this CV outcomes trial will be a required postmarketing trial.”

But Hepatic, Cancer Concerns Worry

Although dapagliflozin’s premarketing CV profile looks clean, “several unexpected safety issues identified in this clinical development program were of sufficient concern to FDA to merit discussion of their impact on the overall benefit-risk consideration,” Dr. Parks writes.

Among these are the drug’s hepatic effects. There were a total of five dapagliflozin-treated patients in the phase IIb/III trials who met the laboratory criteria for Hy’s Law (AST or ALT levels greater than three times the upper limit of normal and elevation of total bilirubin level greater than two times the upper limit of normal). One of these was classified as a “probable” case of drug-induced liver injury.

In their review, Office of Surveillance and Epidemiology hepatologists Leonard Seeff and John Senior noted that in many cases the data were too limited to make a linkage between dapagliflozin and liver damage. Given the importance of recognizing sentinel cases of drug-induced liver injury in registrational trials, “it is prudent to gather more information on all relevant cases as part of an in-depth review of the dapagliflozin [new drug application] in order to assess whether this agent may be hepatotoxic,” they say, adding that careful hepatic monitoring should be performed in any future studies.

The FDA also calls the committee’s attention to numerical imbalances in cases of breast and bladder cancer among dapagliflozin-treated patients.

There were seven bladder cancer cases in dapagliflozin-treated patients at the time of the 4-month safety update, compared with none in the control group. Subsequently, two more cases were reported with dapagliflozin and one with controls. “This can be extrapolated to 207 cases per 100,000 person-year exposure in dapagliflozin-treated patients versus 53 cases per 100,000 person-year exposure in control[s],” the clinical review states.

The findings suggest dapagliflozin could be in for the same type of bladder cancer cloud currently hanging over Actos.

The FDA questions whether detection bias resulting from dapagliflozin’s mechanism of action and related genitourinary adverse effects could have contributed to the imbalance observed.

“More frequent assessments of urinalysis in the dapagliflozin group might result in postbaseline detection of hematuria requiring further work-up and higher rate of cancer diagnosis than control group, which might not have received as extensive monitoring,” the FDA reviewers state.

“In this regard, it is interesting to note that concerns of bladder cancer associated with pioglitazone use arose during premarketing development due to nonclinical findings of bladder cancer in male rodents. This led to a prospective assessment of urine cytology in approximately 1,800 patients in clinical trials up to 1 year [in] duration. Despite similar active surveillance for bladder cancer in pioglitazone and control groups, no clinical cases were detected premarketing. Imbalance of clinical bladder cancer risk with pioglitazone was not observed until after approval.”

There also was an imbalance in the number of breast cancer cases, with nine reported in the dapagliflozin-treated group and none in the control group.

For both types of cancer, the FDA concludes that the numbers observed exceeded the expected number of cases in the type 2 diabetic population. It asks the advisory committee whether any imbalance in baseline factors may have contributed to the findings and whether detection bias was a factor.

The FDA also wants the committee to consider the increase in genital and urinary infections associated with dapagliflozin. Such infections have become a well-known side effect of this class of drugs, given their mechanism of action.

This coverage is provided by “The Pink Sheet.” This news organization and “The Pink Sheet” are owned by Elsevier.